Project Summary This direct Phase II SBIR proposal focuses on the development of recombinant human MG53 (rhMG53), a novel tissue repair protein, as a therapeutic candidate targeting injury of renal epithelium to protect against acute kidney injury (AKI). AKI is commonly encountered in the hospital and outpatient settings and is associated with a high rate of mortality. Currently, there is no effective means for preventing or treating AKI. MG53 is a member of the TRIM-family proteins that participates in repair of injury to the cell membrane, and a vital component for reno-protection under both physiologic and pathophysiologic settings. Research and development effort at TRIM-edicine, a university spin-off biotechnology company, has established the following proof-of-concept data supporting rhMG53 as a potential therapeutic reagent for AKI: First, the chemistry, manufacture and control (CMC) process for rhMG53 has been established that allows for scale-up production of rhMG53 to support our pre-clinical and future clinical studies. Second, preliminary toxicological studies in rodent and dog models support the safety for systemic application of rhMG53. Third, transgenic mice with sustained elevation of MG53 in the bloodstream are healthy with enhanced lifespan and display remarkable tissue healing capacity. Fourth, pilot study with a canine model of AKI shows that prophylactic administration of rhMG53 can preserve kidney function following ischemia reperfusion injury. Studies proposed in this SBIR project involve joint development efforts between TRIM-edicine and The Ohio State University, aiming to accomplish the IND-enabling studies for developing rhMG53 as an injectable therapeutics for AKI treatment. Five milestones with deliverable criteria are proposed in this application: to complete the CMC for producing sufficient rhMG53 protein to support pre-clinical, toxicological and human clinical trials (Milestone 1), to develop assays for quality control of rhMG53 (Milestone 2), to establish the pharmacodynamic property of rhMG53 in the canine model of AKI (Milestone 3), to conduct safety and toxicological evaluation of rhMG53 per FDA guidance (Milestone 4), and to assemble IND for rhMG53 in AKI treatment (Milestone 5). Completion of these milestones will enable us to file an IND application to the FDA for initiating a Phase 1 clinical trial for conducting an ?ascending dose study of the safety of a single intravenous infusion of rhMG53 in human subjects with stable ischemic heart diseases who are at risk of developing AKI during cardiothoracic surgery?.